Peritoneal dialysate

ABSTRACT

This invention provides a safe and highly stable peritoneal dialysate, which causes neither peritoneal membrane disorders nor peritoneal sclerosis associated with frequently repeated peritoneal dialysis treatment, which can protect residual renal functions in chronic renal failure, which inhibits the progress of renal damage over a long period of time, and which enables peritoneal dialysis treatment of diabetic patients. This peritoneal dialysate contains 0.05 to 3.5 w/v % of taurine and 0.1 to 6.5 w/v % of trehalose as osmotic agents and has a pH value adjusted between 6.5-7.5.

TECHNICAL FIELD

This invention relates to peritoneal dialysate used for peritonealdialysis.

BACKGROUND ART

Peritoneal dialysis is a therapeutic procedure in which waste productsare drawn from bodily fluids across the peritoneum and into peritonealdialysate by leaving, for a given length of time, peritoneal dialysatesufficiently injected into the abdominal cavity of a renoprival patientwith acute or chronic kidney failure. It further has a purpose ofregulating the balance of the components of the various body fluidsthrough the medium of the therapeutic procedure. The peritoneal dialysisis generally carried out using a liquid solution referred to asperitoneal dialysate.

As one example of the liquid solutions, there is enumerated a dialysatesolution for continuous ambulatory peritoneal dialysis (CAPD). There hasbeen reported a dialysate solution which typically contains lactate saltas an alkaline agent and hydrogen carbonate in order for maintaining apH value approximate to the body fluid, as well as electrolytecompositions such as sodium chloride, calcium chloride and magnesiumchloride and further contains glucose as an osmotic agent for keepingthe osmotic pressure higher than the body fluid in order to secureultrapermeability of the dialysate solution (Patent Reference 1).

Patent Reference 1: Japanese Published Unexamined Application No.2000-51348

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

However, peritoneal dialysate containing glucose, as described in PatentReference 1, has a problem such that hyperglycemia attributable toglucose present at high concentration affects the whole body andmetabolism. Particularly, since cases of kidney failure caused bydiabetes have been remarkably increasing as of late, there is concernabout the use of glucose for the peritoneal dialysate as it mayaggravate kidney failure.

Further, when a glucose solution is adjusted to have a pH value of 6.0to 7.5, with an aim to come into a neutral to alkaline state close to aphysiologic condition, a subset of glucoses are polymerized with oneanother or react with residual trace substances when sterilized at ahigh temperature, consequently tingeing the glucose solution.Particularly when a small amount of amino acid is resident in thesolution, a dramatic browning Maillard reaction occurs, and further,glucose decomposition products having peritoneal cytotoxicity areproduced.

The use of glucose suffers from the disadvantage that glucose isdecomposed at a neutral pH or a slightly alkaline pH to increase5-hydroxymethylfurfural (5-HMF), formic acid, aldehydes and others,consequently decreasing the pH value with time. These decompositionproducts have cytotoxic activity and may contribute to the developmentof complications such as amyloidosis and accelerated arteriosclerosis.

In order to suppress the aforementioned reaction, the pH value of theperitoneal dialysate is reduced to around 5.0, but a patient undergoingperitoneal dialysis at a low pH is constantly exposed to the acidicsolution of highly concentrated glucose. Additionally, since glucosereacts, due to its carbonyl radical, with free amino acids of aminoacid, peptides and proteins or phospholipids of the peritoneum, theperitoneum is damaged by long-term use of the highly concentratedglucose solution. This can lead to peritoneal deterioration and evenperitoneal sclerosis.

To solve these problems, a glucose-replacing osmotic agent has beenproposed. For instance, trehalose is widely distributed in the animalkingdom and is a stable disaccharide which is easily metabolized insidethe body and also used to prevent adhesion at surgical sites. PatentReference 2 discloses a peritoneal dialysate containing trehalose as anosmotic agent. Patent Reference 3 discloses a peritoneal dialysatecontaining trehalose as an osmotic agent and glucose as an energysource.

One of the inventors of this invention has disclosed a peritonealdialysate in which taurine is selected as an osmotic agent (PatentReference 4). Taurine is a non-protein amino acid and has been confirmedto oppose changes in osmotic pressure of the body fluid by increasingits intracellular concentration, thereby protecting cells. Taurine hasfurther been confirmed by a load test to be considerably safe forhumans. In addition, a peritoneal dialysis patient has a low taurineconcentration in blood plasma and muscles due to synthesis inhibition,and thus it is effective to supply the taurine to the patient throughthe medium of the dialysate. Taurine may also have secondary effects ofimproving circulatory function and fat metabolism and diuretic activity,as well as being suitable for peritoneal dialysis.

Patent Reference 2: Japanese Published Unexamined Application HEI07-323084

Patent Reference 3: Japanese Published Unexamined Application No.2002-282354

Patent Reference 4: Japanese Published Unexamined Application No.2005-531630

However, the peritoneal dialysate as described in Patent References 2-4cannot be said to be a perfect replacement for peritoneal dialysatecontaining glucose, which has been the type of dialysate mainly used todate. The peritoneal dialysate described in Patent Reference 3 istypically used with a mixture of glucose, which has long been used, andtrehalose, but problems potentially caused by the use of glucose, suchas peritoneal injury and hyperglycemia, remain.

Although the peritoneal dialysate described in Patent References 2 and 4is free of glucose, it has to contain an osmotic agent in relativelyhigh concentration when only one osmotic agent is used. In that case,when the dialysate flows rapidly into the blood due to weakening of theperitoneum, which is possibly caused by frequent dialysis, thepossibility of allowing high levels of agent to destabilize bodilymetabolism is undeniable. In addition, it cannot be denied that when onesubstance assumes all the osmotic activities, the possibility of causinga change in pH and a reaction of contained material due to unexpectedextracorporeal factors or intracorporeal factors during dialysis maypose a risk to the dialysis patient. To date, peritoneal dialysatecontaining osmotic agents other than glucose have not commonly beenused, primarily because its biosafety for long-term use has notsufficiently been confirmed.

Peritoneal dialysate safe for use in a chronic renal failure patient isessentially required to have an appropriate osmolar design andcharacteristics for peritoneal dialysis, and function to sufficientlytreat a renal failure patient without producing the various injuriouseffects caused by inclusion of glucose. Further, it must assure liberalsafety. That is, it needs to be exceptionally stable so as to provideand maintain the optimal osmotic pressure and pH for ensuring safety inthe body.

Such being the case, the inventors of this invention investigated asolution to the aforementioned problems by concomitant use of taurineand trehalose as osmotic agents. Taurine and trehalose can both safelymaintain blood metabolic activity even when the blood concentrationtemporarily increases due to weakening of the peritoneum or othercauses. At that time, if the concentration of each substance can bedecreased without singly using one of the substances at highconcentration, any impact on metabolism can be diminished so as toincrease the safety. Both substances are equivalent as the osmotic agentand additively involved in the osmotic pressure, but they aremetabolically different from each other, so that safety and stabilitycan be improved synergistically by being kept at low concentrationrespectively.

In order to solve the above problems, the present invention seeks toprovide peritoneal dialysate having little peritoneal cytotoxicity,being neutral (pH 6.5 to 7.5), having few side-effects and superiorphysicochemical stability, causing little biological perturbation, andbeing capable of satisfactorily attaining a blood purification effectfor removing urea or urea-derived nitrogen-containing compounds to betreated and a dewatering effect by containing, as an osmotic agent,multiple innocuous natural ingredients other than glucose.

Means for Solving the Problems

To attain the object described above, the peritoneal dialysate accordingto the present invention comprises the following characteristic means:

That is, the peritoneal dialysate of the present invention ischaracterized by comprising 0.05 to 3.5% w/v of taurine and 0.1 to 6.5%w/v of trehalose and being pH 6.5 to 7.5.

Further, the peritoneal dialysate of the present invention ischaracterized by using taurine and trehalose as osmotic agents andhaving osmotic pressure of 300 to 680 mOsm/L based on extracellularfluid.

Further, the peritoneal dialysate of the present invention ischaracterized by comprising taurine, trehalose, amino acids, minerals,vitamins and an alkaline agent.

Further, the peritoneal dialysate of the present invention ischaracterized by containing an amino acid selected from L-histidine,L-isoleucine, L-leucine, L-valine, L-tyrosine, L-arginine, L-tryptophan,L-lysine, L-methionine, L-phenylalanine, L-threonine, L-glutamine,L-glutamic acid, and L-carnitine, and at least L-histidine,L-isoleucine, L-leucine, L-valine, L-tyrosine, and L-arginine, andhaving an amino-acid concentration of 0.4 to 5.0% by weight in sumtotal.

Further, the peritoneal dialysate of the present invention ischaracterized by containing, as the minerals, three or more kindsselected from ferric iron, copper ion, calcium ion, magnesium ion, zincion, chromium ion, selenium ion, and manganese ion.

Further, the peritoneal dialysate of the present invention ischaracterized by containing, as the vitamins, at least four or morekinds selected from vitamin A, vitamin D3, vitamin E, vitamin B1 ,vitamin B2, niacin, vitamin B6 and its derivative, folic acid, vitaminB12, pantothenic acid, vitamin C and its derivative, wherein the totalamount of the vitamins is 10 to 40 mg.

Further, the peritoneal dialysate of the present invention ischaracterized by containing bicarbonate as the alkaline agent, whereinthe pH value thereof is adjusted to 6.5 to 7.5 in use.

Effect of the Invention

The present invention formulated as above brings about the followingeffects.

According to the present invention, the peritoneal dialysate suitablefor use in peritoneal dialysis can be obtained by mixing both osmoticagents while adjusting the ratio of concentration in the range of 0.05to 3.5% w/v of taurine and 0.1 to 6.5% w/v of trehalose, so that theosmotic pressure can be adjusted arbitrarily within a range capable ofensuring a dewatering amount sufficient for dialysis to an extent ofcausing no water loss. The peritoneal dialysate obtained by mixing theosmotic agents at the aforementioned ratio of concentration cansynergistically protect and preserve the peritoneal tissue by the actionof protecting and repairing tissue and cells by distinctive functions ofthe osmotic agents while providing an osmotic pressure effect by virtueof each of the substances contained therein, consequently preventingdevelopment of a disorder. More stable and safe osmotic pressure can beretained against unexpected disorders caused by relying on only oneosmotic agent.

The peritoneal dialysate according to the present invention does notrequire the addition of glucose as an osmotic agent, thus removing anyneed to make the pH value acidic in order to prevent undesirablechemical reactions of glucose. This allows for a pH value of 6.5 to 7.5,which is close to physiological conditions, thereby obviating the riskto the dialysis patient of any shock brought on by an acidic solution.Further, this avoids disorders arising from chemical reactants ofglucose and elevation of blood sugar level, so that the peritonealdialysis can be carried out more safely over a prolonged period.

The peritoneal dialysate according to the present invention can providesafety in excess of a established ranges of conventional dialysis byestablishing the minimum limit value of osmotic pressure at 300 mOsm/L.The maximum limit value of osmotic pressure is set to 680 mOsm/L, whichdoes not cause rapid dewatering, so that an optimum dewatering speed forperforming peritoneal dialysis can be achieved.

The peritoneal dialysate according to the present invention contains allor part of amino acids, minerals and vitamins, so that furnishing ofnutrition can be performed through dialysis, consequently protecting apatient from nutritional deficiency and defective metabolism caused bydialysis. Particularly, since glucose is not used as an osmotic agent,there is no need to worry about the carbonyl group of glucose reactingwith various amino acids, peptides and other proteins (various types ofmembrane proteins such as hemocyte membrane). Furthermore, the osmoticagent does not mutually react with these added nutrients by virtue ofthe pH stability brought about by the alkaline agent, so that it can bemaintained stably.

According to the peritoneal dialysate of the present invention, aminoacids can be added for nutritional support because the osmotic agentsare both unresponsive to amino acids. The profile of amino acids used tosupplement the peritoneal dialysate of the invention has thesignificance of not merely adding amino acids, centered around theessential amino acids, for the purpose of conserving and fortifyingprotein nutrition, but also coping with the imbalance of amino-acidmetabolism resulting from organ dysfunction such as renal failure.Leucine, isoleucine and valine, which are branched-chain amino acids andconstituent elements of muscle, serve to alleviate muscle depletioncaused by a low protein diet in patients with renal failure. Histidineis synthesized into muscle protein and it is one of blood pigmentcomponents, so that it can be suitably prescribed for an anemiccondition. Arginine, which is reduced in synthesis due to renal failure,is important for maintaining immunity activity and indispensable fornitrogen metabolism and has a vasodepressor effect and aninsulin-secretion stimulating effect. Tyrosine, as a precursor of aneurotransmitter, serves to supplement the activities of the nervoussystem. By adding a suitable quantity of amino acids to the peritonealdialysate, aggressive therapy can be provided for improving metabolismand aiming to maintain and preserve nephron function by using the sameperitoneal dialysate, thus defining new dimensions in dialysis therapyfor renal failure. Hence, there is no precedent for amino-acid additionto the peritoneal dialysate for furnishing nutrition and fulfilling aspecific function for therapeutic applications.

According to the peritoneal dialysate of the present invention,essential trace minerals such as copper, zinc, manganese, chromium andselenium, in addition to calcium, magnesium and iron, can be added tothe peritoneal dialysate. The minerals are indiscriminately excreted anddrawn into the dialysate during peritoneal dialysis therapy, potentiallyleading to an increased burden on a dialysis patient due to alimentarydeficiency and enhanced general fatigue. The ferric ion and copper ionas disclosed in this invention are added for coping with ferric-ion orcopper-ion deficiency anemia, and the calcium ion is added for itsprotective effect against osteoporosis. The magnesium ion is added forbiomembrane conservation and normalization of energetic metabolism ormuscular movement, the zinc ion is added for preventing outbreak ofdermatitis and conserving immunity, and the chromium ion is added forpreventing peripheral nerve impairment and decreased carbohydratetolerance. The selenium has a function of suppressing development ofcardiomyopathy and leg myalgia. There has not yet been such a peritonealdialysate containing these essential trace minerals.

The peritoneal dialysate of the invention can contain vitamins becauseglucose is excluded, which allows for making the pH value neutral. Thus,the dialysis patient can be protected from vitamin deficiency resultingfrom diet restriction. Since it is specifically possible to add avitamin B6 derivative, it should be feasible to eliminateglucose-derived harmful substances such as GDP (glucose degradationproducts) and AGE (advanced glycation end-products), thereby potentiallyreducing the risk of peritoneal sclerosis. The addition of vitamins tothe conventional peritoneal dialysate has never been taken intoconsideration.

The peritoneal dialysate of the invention can be stably kept at aneutral pH value close to physiological conditions by the use ofbicarbonate as the alkaline agent. The constituents of the peritonealdialysate of the present invention set forth in claims 1 to 6 caneliminate the need for lowering the pH value to ensure stability whendissolving the dialysate, so that the pH value can be adjusted within aneutral range, thereby making the dialysate stable. Though there islittle possibility of dramatically departing from the range ofphysiological conditions, the fact that the peritoneal dialysate of theinvention already contains the alkaline buffering agent means that thepH value can be kept within a safer range should any unanticipatedsituations arise during use. Further, by selecting as the alkaline agentbicarbonate, which serves in vivo as a pH buffering agent for blood, thedialysate more closely resembles the internal environment of the livingorganism.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described hereinafter in detail.

The trehalose subsumes, as its isomer, α,β-trehalose and β,β-trehalose.As the osmotic agent, the natural α,α-trehalose is used in thisinvention. Taurine and trehalose do not react mutually with each other,so these osmotic agents can be mixed at an arbitrary concentration andat an arbitrary ratio of concentration designed for the peritonealdialysate. Because the aforementioned trehalose is a disaccharide, itsuse as an osmotic agent must be at double the concentration of amonosaccharide, such as glucose, in order to possess equivalent osmoticactivity.

The contained amount of the osmotic agents is 0.05 to 3.5% w/v oftaurine and 0.1 to 6.5% w/v of trehalose. In case of a concentrationhigher than this, the dewatering amount becomes excessive, which canlead to various symptoms associated with water loss. The excessdewatering may potentially cause peritoneal sclerosis due to chronicosmotic stress. To determine a concentration at which osmotic pressureproduces a satisfactory dialyzing effect, and at which dewatering is notcaused excessively, it is preferable to specify a range of 0.1 to 3.0%w/v of taurine and 0.2 to 6.0% w/v of trehalose, more preferably, 0.3 to2.5% w/v of taurine and 0.6 to 5.0% w/v of trehalose, for obtaining aneffectual dewatering amount.

The osmotic pressure of the peritoneal dialysate is adjusted bysubstantially controlling the concentration of the osmotic agents, i.e.taurine and trehalose, or adjusting the ratio of concentration of bothosmotic agents. Upon withholding the contribution of all other dissolvedsubstances to the osmotic pressure, the osmotic pressure of thedialysate can be defined by taurine and trehalose as the osmotic agents,but the mixing ratio (molar ratio of concentration) of both substancesmay be determined to 10:1 to 1:10. The concentration of both substancesmay more preferably be determined to be kept close to an equal moleratio of concentration.

The osmotic pressure defined by the addition of all components isrequired to be in a range of 300 to 680 mOsm/L. When the osmoticpressure is less than 300 mOsm/L, the dewatering amount hardly reachesthe required amount. When a mixture of the osmotic agents having aconcentration of no less than 680 mOsm/L is used, the dewatering amountbecomes excessive, which can lead to the development of various symptomsassociated with water loss. It is more preferable to make the osmoticpressure between 320 mOsm/L and 650 mOsm/L, so as to provide asufficient dewatering amount, thereby avoiding rapid dewatering, whichacutely causes physiological impact, and preventing peritoneal sclerosisdue to chronic osmotic stress. The osmotic pressure in the range of 330to 530 mOsm/L is particularly advisable for carrying out gradualdewatering.

The amino acids to be added to the dialysate are selected fromL-histidine, L-isoleucine, L-leucine, L-valine, L-tyrosine, L-arginine,L-tryptophan, L-lysine, L-methionine, L-phenylalanine, L-threonine,L-glutamine, L-glutamic acid, L-proline and L-carnitine. Theparticularly desirable concentration of the amino acids may be achievedby using six or more components of 0.02 to 0.13% w/v of L-histidine,0.085 to 0.50% w/v of L-isoleucine, 0.07 to 0.8% w/v of L-leucine, 0.05to 0.5% w/v of L-valine, 0.02 to 0.15% w/v of L-tyrosine, 0.025 to 0.6%w/v of L-arginine, 0.02 to 0.20% w/v of L-tryptophan, 0.02 to 0.3% w/vof L-methionine, and 0.05 to 0.5% w/v of L-camitine. The concentrationof each amino acid shows a desirable concentration for restoring theaminogram of a patient undergoing dialysis therapy to the normal range.If the concentration is excessive, the increased risk of causingacidosis requires attention. A variety of investigations have found thatthe concentration of the amino acid to be added should be 0.4 to 5.0%w/v in terms of the total amount of amino acid, more preferably, 0.7 to3.0% w/v for lessening the risk of metabolic acidosis.

The dialysate for a one-time use preferably contains, as the minerals,ferric iron (0.1 to 3 mg), copper ion (0.1 to 0.7 mg), chromium ion (0.1to 50 μg), manganese ion (0.1 to 0.5 mg), selenium ion (0.1 to 20 μg),calcium ion (1.0 to 10.0 mg), magnesium ion (0.2 to 4.0 mg), and zincion (0.2 to 2.0 mg). Although the water-soluble essential trace mineralsin the blood are lost due to the peritoneal dialysis, the amount ofmetals to be replenished as additives to the dialysate conforms to‘Nutritional Requirements of Japanese (Sixth Edition)’.

Vitamins should be offered for compensating for components lost withdewatering during peritoneal dialysis therapy. In particular, vitamin B6derivatives are useful for enhancing an antioxidant effect. As to thetypes and the additive amounts of the respective vitamins to be addedper one dose of dialysate, the dialysate may preferably contain six ormore of vitamin A (100 to 2000 I.U.), vitamin D3 (10 to 200 I.U.),vitamin E (0.5 to 10 mg), vitamin B1 (0.2 to 5.0 mg), vitamin B2 (0.5 to5 mg), niacin (2) to 10 mg), vitamin B6 and one or two or morederivatives thereof, i.e. pyridoxine, pyridoxal, pyridoxamine, andpyridoxal phosphate, (0.2 to 10 mg, respectively), folate (50 to 200μg), vitamin B12 (1.0 to 5.0 μg), pantothenic acid (0.5 to 5 mg), andvitamin C or ascorbic acid 2-glucoside (20 to 100 mg). The amountsdefined herein conform to those described in the ‘NutritionalRequirements of Japanese (Sixth Edition)’ and suffice to replenish theamounts and qualities of the components lost during peritoneal dialysis.

The pH value of the peritoneal dialysate is determined and maintained inthe range of 6.5 to 7.5. Although the present invention employs, as thealkaline agent, hydrogen carbonate, which serves as a blood-bufferingagent in vivo, lactate salt and citric salt may be used as well.Electrolytes generally used in peritoneal dialysis include, e.g., sodiumion, calcium ion, magnesium ion, zinc ion, and chlorine ion. Electrolytecompositions containing sodium chloride, calcium chloride, magnesiumchloride and zinc sulfate are preferable. Taurine and trehalose asosmotic agents can be maintained stably in the above-mentioned pH range,consequently avoiding reactions with other components of the dialysate,interperitoneal compositions or peritoneal cells.

The compounding amount of each of the components contained in theperitoneal dialysate may preferably be determined in the concentrationrange as enumerated below.

Sodium ion 50 to 150 mEq/L Potassium ion 0 to 3.0 mEq/L Chlorine ion 50to 140 mEq/L Alkaline agent 2.0 to 45 mEq/L Total of trehalose andtaurine 0.6 to 9.0% w/v Total of amino acids 0.4 to 5.0% w/v

The peritoneal dialysate is stored in a plastic container made of, e.g.,polyethylene, polypropylene, polyvinyl chloride, polyester,ethylene-vinyl acetate copolymer, nylon, or complex material thereof.The present invention containing a mixture of trehalose and taurine asthe osmotic agents in place of glucose may be stored in a containerhaving a single compartment as a neutral dialysate without peritonealcytotoxicity. However, if the need arises, the dialysate may also beformulated for storage in containers with two or more compartments.

Sterilization may be performed under ordinary heat sterilizationconditions at 108 degrees C. for 60 minutes, but use of atemperature-resistant container enables ‘all kill’ sterilization. Ofcourse, other sterilization methods may be applied, e.g., asepticfiltration sterilization and radiosterilization using ultraviolet ray orgamma ray. The invention can be put to practical use in such a mannerthat CAPD dialysate is put in a plastic container having no gas-barrierproperty and covered with a gas-barrier packing material on the outside,or it can be stored in a gas-barrier plastic container. The term‘material having gas-barrier property’ means a material havingnon-permeability or little permeability to gases such as oxygen,nitrogen, carbon dioxide and water vapor. The term ‘gas-barrier plastic’means, for instance, ethylene-vinyl alcohol copolymer, polyvinylidenechloride, gas-barrier nylon or other polymers. The optimal gas-barrierplastic can be selected from these materials so as to gain anappropriate degree of polymerization. The gas-banier plastic may be madeby laminating or coating a plastic base with these materials, or bylaminating or coating with aluminium, aluminum oxide, silicon oxide orthe like. Transparency and opacity thereof do not matter.

In case a gas-barrier packing material is used as an outer packingmaterial, a space between the container storing the peritoneal dialysateand the outer packing material may be filled with an inert gas, or amoderately concentrated mixture of inert gases, such as nitrogen gas andcarbon dioxide or sealed in a de-aerated state.

Embodiment

Hereinafter, preferred embodiments of the invention will further bedescribed in detail, but the invention is not to be considered limitedto these embodiments.

Embodiment 1: (Stability with Respect to Heat Sterilization)

A solution was made by dissolving, into a suitable quantity of distilledwater for injection, 107.8 g of sodium chloride, 5.14 g of calciumchloride dihydrate, 1.016 g of magnesium chloride hexahydrate, 5.4 g ofacid sodium carbonate, 5.6 g of L-histidine, 3.8 g of L-tryptophan, 15.0g of L-isoleucine, 12.4 g of L-leucine, 9.4 g of L-valine, 4.3 g ofL-tyrosine, and 9.4 g of L-arginine, and adjusting the pH value to 7with sodium hydrate, followed by adding water up to 20 liters in volume.The solution thus obtained was designated as a basic solution. The basicsolution in this embodiment does not contain vitamins. Test solutionsTT-1, TT-2, TT-3, TT-4 and Glue are shown in the following Table 1.

TABLE 1 Measurement Item Absorbance Test Solutions Measuring Time pH(430 nm) Osmotic Pressure Aspect Basic Solution Before sterilization7.05 0.005 309 Transparent After sterilization 6.85 0.000 312Transparent TT-1 Before sterilization 7.21 0.009 405 Transparent Aftersterilization 6.93 0.019 407 Transparent TT-2 Before sterilization 7.010.002 458 Transparent After sterilization 6.85 0.008 460 TransparentTT-3 Before sterilization 6.98 0.003 521 Transparent After sterilization6.72 0.024 524 Transparent TT-4 Before sterilization 7.15 0.000 395Transparent After sterilization 6.95 0.011 394 Transparent ComparisonBefore sterilization 7.65 0.000 512 Transparent Solution Gluc. Aftersterilization 7.55 0.126 516 Colored (Yellow) Basic solution: 20 litersof distilled water for injection, containing only salts and amino acidsand having pH 7.4. TT-1: Basic solution (1L) + Taurine (10.0 g) +Trehalose (10.0 g) TT-2: Basic solution (1L) + Taurine (15.0 g) +Trehalose (15.0 g) TT-3: Basic solution (1L) + Taurine (30.0 g) TT-4:Basic solution (1L) + Trehalose (30.0 g) Gluc.: Basic solution (1L) +Glucose (38.0 g) Sterilization Condition: 108 degrees C. for 60 minutesPreservation Condition: Left at 60 degrees C.

As is evident from the results shown in Table 1, the test solutions TT-1to TT-4 changed little in aspect, pH value and osmotic pressure evenafter high-pressure steam sterilization and storage at 60 degrees C. fortwo weeks, and the stability of the test solutions could be maintained.On the other hand, a comparison solution containing glucose underwent asevere browning reaction after high-pressure steam sterilization,thereby leading to a lower pH value. After storing for two weeks, thisglucose-containing solution developed a tendency to brown further anddecrease the pH value yet more.

EMBODIMENT 2: (Relation between Concentration and Dewatering Amount)

A solution was regulated in quantity by dissolving, into distilledwater, sodium chloride (5.38 g), sodium hydrogen carbonate (2.52 g),magnesium chloride hexahydrate (34 mg), calcium chloride dihydrate (370mg), and zinc sulfate heptahydrate (86 mg), so as to have a pH value of7.2, and adding distilled water up to 1 liter of the regulated solution.The obtained solution was designated as a basic solution. To the basicsolution, 2.0 g of L-arginine, 0.5g of L-histidine, 3.0 g of L-leucine,2.0 g of L-isoleucine, 2.0 g of L-valine and 0.5 g of L-tyrosine wereadded, and further, taurine and trehalose were added to obtain testsolutions TTA-3 to TTA-6. Comparison solutions GLU-1, GLU-2 and GLU-3were prepared by dissolving glucose into the basic solution. Thesolutions TTA-1 and TTA-2 each had an amino-acid concentration half ofthat of the respective TTA-3 to 6. Upon injecting the solutions eachwere injected into the abdominal cavity of a male SD rat, the fluidvolume of each solution injected into the abdominal cavity was measuredto determine a dewatering amount based on a difference between themeasured volume and the injected volume (30 ml).

The results are shown in Table 2.

TABLE 2 Osmotic Agent (g/L) Average Dewatering Amount (ml) Osmotic AminoAcid Taurine Trehalose Glucose Average Minimum Maximum Pressure BasicSolution 0 0 0 0 −5.16 −5.31 −5.03 251.9 TTA-1 5 0.03 0.06 0 −2.43 −3.03−2.1 288.7 TTA-2 5 0.50 1.00 0 −1.84 −1.89 −1.53 295.1 TTA-3 10 3.754.25 0 0.58 0.19 0.76 330.0 TTA-4 10 3.75 10.80 0 4.23 3.74 4.53 384.7TTA-5 10 5.62 5.40 0 4.57 4.33 4.75 385.3 TTA-6 10 7.50 10.80 0 6.716.47 6.90 414.7 TTA-7 10 10.00 14.40 0 8.57 8.32 9.25 446.6 GLU-1 0 0 013.6 0.61 −0.11 0.30 327.5 GLU-2 0 0 0 22.7 4.26 3.80 4.63 378.1 GLU-3 00 0 38.6 11.54 11.29 11.79 466.4

As shown in Table 2, the peritoneal dialysate containing the osmoticagent prepared by mixing taurine, trehalose, and six types of aminoacids can bring about concentration-independent osmotic pressure, aswell as a solution containing glucose as the osmotic agent, so that adesirable dewatering effect can be achieved by control of concentration.

Embodiment 3: (Peritoneal Cytotoxicity)

It is a basic requirement for the peritoneal dialysate that theperitoneum is maintainable in its dewatering function over a lengthyperiod without being harmed by repeated injection, dwelling and drainageof the peritoneal dialysate relative to the peritoneum. For acomparative investigation of peritoneal cytotoxicity, the followingexperimental conditions are provided. To be specific, a given volume (30ml) of testing peritoneal dialysate was injected into the abdominalcavity of a rat, and subsequently drained following a dwelling time of agiven length (four hours). Subsequently, the same volume of otheridentical peritoneal dialysate was injected into the abdominal cavityand all drained following a dwelling time of a given length (fourhours). This procedure was performed three times a day and continued forseven days. When the peritoneum is damaged, the dewatering competence isreduced according to extent of damage, thus, the peritoneal cytotoxicityof the testing peritoneal dialysate can be evaluated by injecting anassay reagent (30 ml) containing xylitol having a fixed concentrationinto the abdominal cavity on the eighth day after start of the test, andthen draining the solution after the elapse of a given dwelling time(four hours), after which the volume of the drained solution and theconcentration of xylitol can be measured. For use as the testingperitoneal dialysate, the peritoneal dialysate TTA-3 according to theinvention (cf. Embodiment 2) was used, and as the comparison solution, acommercially available peritoneal dialysate containing 2.27% of glucosewas used. Using five male SD rats (with weight of 250 up to 300 g),injection and drainage of 30 ml of the testing peritoneal dialysate andthe same quantity of comparison solution were repeatedly performed threetimes a day for seven days, and on the eighth day after start of thetest, 30 ml of 1.9% w/v testing xylitol solution (special grade xylitolmade by Wako Pure Chemical Industries, Ltd.) was injected into theabdominal cavity of the rats. Just after injection, a specimen wascollected and, after being left for four hours, again collected in orderto measure the concentration of xylitol, and then all of the solutionwas drained to measure the volume of the discharged solution. Assumingthat the volume of xylitol just after injection is D0 and the volume ofthe same after being left for four hours is D4, profuse dispersal ofxylitol outside the peritoneum, as shown by the ratio of D4/D0decreasing, indicates the possibility of disease or disorder of theperitoneum.

TABLE 3 Quantitative Ratio D 4/D 0 (N = 5) Testing Peritoneal DialysateXylitol 2.27% Glucose-Containing Commercial Volume (g) TTA-3 PeritonealDialysate D 0 0.564 ± 0.012 0.564 ± 0.014 D 4 0.133 ± 0.012 0.080 ±0.015 D 4/D 0 0.235 ± 0.024 0.142 ± 0.022

As shown in Table 3, the xylitol quantitative ratio D4/D0 relative toTTA-3 according to the invention significantly indicates an elevatedlevel compared with the commercially available peritoneal dialysate(containing 2.27% of glucose) (P<0.001). That is, even with frequent,repetitive injection and drainage of the peritoneal dialysate TTA-3relative to the abdominal cavity, the amount of peritoneal dialysateoutflowing from the abdominal cavity into the blood vessel through theperitoneum is significantly smaller than that in the case of using theglucose-containing peritoneal dialysate, indicating little, if any,disease or disorder of the peritoneum.

INDUSTRIAL APPLICABILITY

The peritoneal dialysate according to the invention has superiorphysicochemical stability and causes little biological perturbation,does not involve peritoneal degradation, has fewer side-effects and,further, can attain a satisfactorily therapeutic blood purificationeffect for removing urea or urea-derived nitrogen-containing compoundsand a dewatering effect, so that dialysis treatment can safely beprovided for a renal failure patient for long periods.

1. Peritoneal dialysate comprising 0.05 to 3.5% w/v of taurine and 0.1to 6.5% w/v of trehalose and being pH 6.5 to 7.5.
 2. Peritonealdialysate comprising taurine and trehalose as osmotic agents and havingosmotic pressure of 300 to 680 mOsm/L based on extracellular fluid. 3.The peritoneal dialysate set forth in claim 1 or claim 2, furthercontaining amino acids, minerals and vitamins.
 4. The peritonealdialysate set forth in claim 1 or claim 2, further containing aminoacids selected from L-histidine, L-isoleucine, L-leucine, L-valine,L-tyrosine, L-arginine, L-tryptophan, L-lysine, L-methionine,L-phenylalanine, L-threonine, L-glutamine, L-glutamic acid, L-prolineand L-carnitine, and at least L-histidine, L-isoleucine, L-leucine,L-valine, L-tyrosine, and L-arginine, and having an amino-acidconcentration of 0.4 to 5.0% w/v by weight in sum total.
 5. Theperitoneal dialysate set forth in claim 3, further containing aminoacids selected from L-histidine, L-isoleucine, L-leucine, L-valine,L-tyrosine, L-arginine, L-tryptophan, L-lysine, L-methionine,L-phenylalanine, L-threonine, L-glutamine, L-glutamic acid, L-prolineand L-carnitine, and at least L-histidine, L-isoleucine, L-leucine,L-valine, L-tyrosine, and L-arginine, and having an amino-acidconcentration of 0.4 to 5.0% w/v by weight in sum total.
 6. Theperitoneal dialysate set forth in claim 1 or claim 2, furthercontaining, as the minerals, three or more kinds selected from ferriciron, copper ion, calcium ion, magnesium ion, zinc ion, chromium ion,selenium ion, and manganese ion.
 7. The peritoneal dialysate set forthin claim 3, further containing, as the minerals, three or more kindsselected from ferric iron, copper ion, calcium ion, magnesium ion, zincion, chromium ion, selenium ion, and manganese ion.
 8. The peritonealdialysate set forth in claim 4, further containing, as the minerals,three or more kinds selected from ferric iron, copper ion, calcium ion,magnesium ion, zinc ion, chromium ion, selenium ion, and manganese ion.9. The peritoneal dialysate set forth in claim 5, further containing, asthe minerals, three or more kinds selected from ferric iron, copper ion,calcium ion, magnesium ion, zinc ion, chromium ion, selenium ion, andmanganese ion.
 10. The peritoneal dialysate set forth in claim 1 orclaim 2, further containing, as the vitamins, at least four or morekinds selected from vitamin A, vitamin D3, vitamin E, vitamin B1,vitamin B2, niacin, vitamin B6 and its derivative, folic acid, vitaminB12, pantothenic acid, vitamin C and its derivative, wherein the totalamount of the vitamins is 10 to 40 mg.
 11. The peritoneal dialysate setforth in claim 3, further containing, as the vitamins, at least four ormore kinds selected from vitamin A, vitamin D3, vitamin E, vitamin B1,vitamin B2, niacin, vitamin B6 and its derivative, folic acid, vitamin B12, pantothenic acid, vitamin C and its derivative, wherein the totalamount of the vitamins is 10 to 40 mg.
 12. The peritoneal dialysate setforth in claim 4, further containing, as the vitamins, at least four ormore kinds selected from vitamin A, vitamin D3, vitamin E, vitamin B1,vitamin B2, niacin, vitamin B6 and its derivative, folic acid, vitamin B12, pantothenic acid, vitamin C and its derivative, wherein the totalamount of the vitamins is 10 to 40 mg.
 13. The peritoneal dialysate setforth in claim 5, further containing, as the vitamins, at least four ormore kinds selected from vitamin A, vitamin D3, vitamin E, vitamin B1,vitamin B2, niacin, vitamin B6 and its derivative, folic acid, vitamin B12, pantothenic acid, vitamin C and its derivative, wherein the totalamount of the vitamins is 10 to 40 mg.
 14. The peritoneal dialysate setforth in claim 6, further containing, as the vitamins, at least four ormore kinds selected from vitamin A, vitamin D3, vitamin E, vitamin B1,vitamin B2, niacin, vitamin B6 and its derivative, folic acid, vitaminB12, pantothenic acid, vitamin C and its derivative, wherein the totalamount of the vitamins is 10 to 40 mg.
 15. The peritoneal dialysate setforth in claim 7, further containing, as the vitamins, at least four ormore kinds selected from vitamin A, vitamin D3, vitamin E, vitamin B1,vitamin B2, niacin, vitamin B6 and its derivative, folic acid, vitamin B12, pantothenic acid, vitamin C and its derivative, wherein the totalamount of the vitamins is 10 to 40 mg.
 16. The peritoneal dialysate setforth in claim 8, further containing, as the vitamins, at least four ormore kinds selected from vitamin A, vitamin D3, vitamin E, vitamin B 1,vitamin B2, niacin, vitamin B6 and its derivative, folic acid, vitamin B12, pantothenic acid, vitamin C and its derivative, wherein the totalamount of the vitamins is 10 to 40 mg.
 17. The peritoneal dialysate setforth in claim 9, further containing, as the vitamins, at least four ormore kinds selected from vitamin A, vitamin D3, vitamin E, vitamin B1,vitamin B2, niacin, vitamin B6 and its derivative, folic acid, vitaminB12, pantothenic acid, vitamin C and its derivative, wherein the totalamount of the vitamins is 10 to 40 mg.
 18. The peritoneal dialysate setforth in claim 1 or claim 2, further containing bicarbonate as thealkaline agent, wherein the pH value thereof is adjusted to 6.5 to 7.5in use.
 19. The peritoneal dialysate set forth in claim 3, furthercontaining bicarbonate as the alkaline agent, wherein the pH valuethereof is adjusted to 6.5 to 7.5 in use.
 20. The peritoneal dialysateset forth in claim 4, further containing bicarbonate as the alkalineagent, wherein the pH value thereof is adjusted to 6.5 to 7.5 in use.21. The peritoneal dialysate set forth in claim 5, further containingbicarbonate as the alkaline agent, wherein the pH value thereof isadjusted to 6.5 to 7.5 in use.
 22. The peritoneal dialysate set forth inclaim 6, further containing bicarbonate as the alkaline agent, whereinthe pH value thereof is adjusted to 6.5 to 7.5 in use.
 23. Theperitoneal dialysate set forth in claim 7, further containingbicarbonate as the alkaline agent, wherein the pH value thereof isadjusted to 6.5 to 7.5 in use.
 24. The peritoneal dialysate set forth inclaim 8, further containing bicarbonate as the alkaline agent, whereinthe pH value thereof is adjusted to 6.5 to 7.5 in use.
 25. Theperitoneal dialysate set forth in claim 9, further containingbicarbonate as the alkaline agent, wherein the pH value thereof isadjusted to 6.5 to 7.5 in use.
 26. The peritoneal dialysate set forth inclaim 10, further containing bicarbonate as the alkaline agent, whereinthe pH value thereof is adjusted to 6.5 to 7.5 in use.
 27. Theperitoneal dialysate set forth in claim 11, further containingbicarbonate as the alkaline agent, wherein the pH value thereof isadjusted to 6.5 to 7.5 in use.
 28. The peritoneal dialysate set forth inclaim 12, further containing bicarbonate as the alkaline agent, whereinthe pH value thereof is adjusted to 6.5 to 7.5 in use.
 29. Theperitoneal dialysate set forth in claim 13, further containingbicarbonate as the alkaline agent, wherein the pH value thereof isadjusted to 6.5 to 7.5 in use
 30. The peritoneal dialysate set forth inclaim 14, further containing bicarbonate as the alkaline agent, whereinthe pH value thereof is adjusted to 6.5 to 7.5 in use.
 31. Theperitoneal dialysate set forth in claim 15, further containingbicarbonate as the alkaline agent, wherein the pH value thereof isadjusted to 6.5 to 7.5 in use.
 32. The peritoneal dialysate set forth inclaim 16, further containing bicarbonate as the alkaline agent, whereinthe pH value thereof is adjusted to 6.5 to 7.5 in use.
 33. Theperitoneal dialysate set forth in claim 17, further containingbicarbonate as the alkaline agent, wherein the pH value thereof isadjusted to 6.5 to 7.5 in use.